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Scott was selected by the Mets in the second round of the 1976 Major League Baseball draft. He made his Major League debut with the Mets in 1979. The Mets traded Scott to the Astros for Danny Heep on December 11, 1982. By the end of the 1982 season, Scott had compiled a 14-27 major league record and was traded from the Mets. Scott continued to struggle in his first two seasons with the Astros, going 15-17.

The turning point in Scott's career came in 1985, when he became a student of legendary pitching coach Roger Craig. Craig taught Scott the split-finger fastball, a pitch he had made famous while coaching the pitchers of the 1984 World Series champion Detroit Tigers. Scott became an 18-game winner in 1985 and was rewarded with a three-year deal with the Astros, valued at $2 million.

Scott enjoyed his most successful season in 1986, when he posted an 18-10 record with a 2.22 ERA, striking out a league-leading 306 batters.[1][2] In addition, on September 25 of that season, he threw a 2-0 no-hitter against the San Francisco Giants at the Astrodome to clinch the National League West division title for the Astros. This game was voted one of the top five games played in the Astrodome after the Astros moved to Enron Field following the 1999 season.[3] He led a strong starting rotation consisting of pitchers Bob Knepper, Nolan Ryan, and Jim Deshaies.

Scott's outstanding form continued into the postseason, when Houston faced the Eastern Division champion New York Mets in the 1986 National League Championship Series. The Astros lost the series, 4 games to 2, but those two Astros' victories were courtesy of Scott's overwhelming starting pitching performances in Games 1 and 4, however there were rumors that Scott's dominating performance was the result of doctoring the baseball or cutting it or "scuffing" it. The New York Mets aggressively voiced their suspicions to the media during the series. In the 2004 book "The Bad Guys Won" by Jeff Pearlman, Scott all but admits to the suspicions. So dominating was Scott against the Mets' batting order in those two games that Game 6 was considered something of a "must win" for the Mets' pennant hopes; a Game 6 loss to the Astros would have meant that New York would again face an apparently unbeatable Mike Scott in a deciding Game 7 in the Astrodome. The Mets did win that Game 6 in sixteen innings—averting another Scott start—to win the league pennant.

In recognition of his regular season performance, Scott was awarded the 1986 National League Cy Young Award as the league's best pitcher. Additionally, Scott was voted the NL 1986 NLCS MVP, the first time in NLCS history that a member of the losing team was so honored (a year later, the San Francisco Giants' Jeffrey Leonard would become the second consecutive NLCS MVP of the losing team).

In 1987, Scott was the National League starter in the All-Star Game, and threw two scoreless innings. He was also the opening day starter for the Astros. He went 16-13 with a 3.23 ERA, eight complete games and three shutouts in 247.2 innings while having 233 strikeouts.

In 1988, Scott once more was named the Astros' opening day starter. On June 12, he was denied a second no-hitter when the Atlanta Braves' Ken Oberkfell singled to right with two outs in the ninth inning. He had a 14-8 record with a 2.92 ERA, eight compete games and five shutouts in 218.2 innings while having 190 strikeouts.

In 1989, Scott won 20 games (while losing 10) and finished second in NL Cy Young Award voting, behind reliever Mark Davis of the San Diego Padres. He was for the third consecutive time, the opening day starter for the Astros. He had a 3.10 ERA, nine complete games and 172 strikeouts in 229 innings played.

Injuries began to plague him shortly thereafter. His 1990 season was his last full season. He had a 9-13 record with a 3.81 ERA in 32 games, having four complete games, two shutouts and 121 strikouts in 205.2 innings. He played in just two games in the 1991 season, losing both games while lasting a total of seven innings, giving up 10 earned runs and having three strikeouts. Scott retired after the 1991 season. As of the 2014 season, Mike is fourth all-time for the Astros in wins (110) and fifth in strikeouts (1318), and sixth in games started (259). "Astros Individual Records".1992 his jersey #33 has been retired by the Astros.[4]